Inappropriate dosing of direct oral anticoagulants: findings from a clinical vignette study and physician survey.

Objective: Direct oral anticoagulants (DOACs) are first-line therapy for stroke prevention for 1.4 million atrial fibrillation (AF) patients in the UK. However, the rates of DOAC dosing below evidence-based recommendations are estimated between 9% and 22%. This study explores specific patient and physician factors associated with prescribing inappropriate DOAC underdoses. Methods: DOAC-prescribing physicians within the UK completed both a clinical vignette survey, which contained 12 hypothetical patient profiles designed to replicate DOAC prescribing scenarios, and a physician survey to capture sociodemographic, clinical experience, and prescriber-related beliefs and motivations related to DOAC prescribing. Eight patient factors based on a literature search and an expert consultation process were varied within the vignettes. Associations between the prescribers' dosing choices and patient factors were explored via multilevel logistic regression. The analysis is focused on the most frequently selected DOACs, apixaban and rivaroxaban, both of which have different dosing guidelines. Results: In all, 336 prescribers (69% male; 233/336) completed the survey, mostly general physicians (GPs) (45%) or cardiology specialists (36%) with a mean of 17.9 years' experience. Most prescribers (73%; 244/336) inappropriately underdosed at least once; rates between GPs and specialists were nearly identical. Patient factors most strongly associated with apixaban inappropriate underdosing included a history of major bleeding and falls. For rivaroxaban, these were major bleeding and severe frailty. Only 32% (106/335) of prescribers reported DOAC dosing guidelines as the sole influence on their prescribing behaviour. Among prescribers who did not inappropriately underdose, greater prescribing confidence was aligned to increased perception of inappropriate underdose risk. Conclusions: Overall, patient factors such as major bleeding and severe frailty were found to be associated with inappropriate underdosing of apixaban and rivaroxaban. Furthermore, prescribers who were more confident in DOAC prescribing, and were more worried about the risk of stroke, were significantly less likely to inappropriately underdose. These findings suggest that all prescribers, regardless of speciality, may benefit from education and training to raise awareness of the risks associated with inappropriate DOAC underdosing.

Outcomes and drivers of inappropriate dosing of non-vitamin K antagonist oral anticoagulants (NOACs) in patients with atrial fibrillation: a systematic review and meta-analysis.

OBJECTIVE: There has been limited systematic evaluation of outcomes and drivers of inappropriate non-vitamin K antagonist oral anticoagulants (NOACs) dosing among patients with atrial fibrillation (AF). This review identified and systematically evaluated literature on clinical and economic outcomes of inappropriate NOAC dosing and associated patient characteristics. METHODS: MEDLINE, Embase, Cochrane Library, International Pharmaceutical Abstracts, Econlit, PubMed and NHS EEDs databases were searched for English language observational studies from all geographies published between 2008 and 2020, examining outcomes of, or factors associated with, inappropriate NOAC dosing in adult patients with AF. RESULTS: One hundred and six studies were included in the analysis. Meta-analysis showed that compared with recommended NOAC dosing, off-label underdosing was associated with a null effect on stroke outcomes (ischaemic stroke and stroke/transient ischaemic attack (TIA), stroke/systemic embolism (SE) and stroke/SE/TIA). Meta-analysis of 15 studies examining clinical outcomes of inappropriate NOAC dosing found a null effect of underdosing on bleeding outcomes (major bleeding HR=1.04, 95% CI 0.90 to 1.19; p=0.625) but an increased risk of all-cause mortality (HR=1.28, 95% CI 1.10 to 1.49; p=0.006). Overdosing was associated with an increased risk of major bleeding (HR=1.41, 95% CI 1.07 to 1.85; p=0.013). No studies were found examining economic outcomes of inappropriate NOAC dosing. Narrative synthesis of 12 studies examining drivers of inappropriate NOAC dosing found that increased age, history of minor bleeds, hypertension, congestive heart failure and low creatine clearance (CrCl) were associated with an increased risk of underdosing. There was insufficient evidence to assess drivers of overdosing. CONCLUSIONS: Our analysis suggests that off-label underdosing of NOACs does not reduce bleeding outcomes. Patients prescribed off-label NOAC doses are at an increased risk of all-cause mortality. These data underscore the importance of prescriber adherence to NOAC dosing guidelines to achieve optimal clinical outcomes for patients with AF. PROSPERO REGISTRATION NUMBER: CRD42020219844.

A RIVA-DM Subanalysis Investigating Patients With Nonvalvular Atrial Fibrillation and Type 2 Diabetes Aged Under Versus Over 80 Years.

BACKGROUND: Advanced age and type 2 diabetes (T2D) are common in patients with nonvalvular atrial fibrillation (NVAF). We evaluated the impact of age on the effectiveness and safety of rivaroxaban versus warfarin in this population. METHODS: We analyzed electronic health record data from November 2010, to December 2019 including adults with NVAF and T2D, newly started on rivaroxaban or warfarin. Propensity score-overlap weighted hazard ratios (HRs) for stroke/systemic embolism (SSE), hospitalization for major or clinically relevant nonmajor bleeding (CRNMB), vascular death, major adverse limb events (MALE), major bleeding, and intracranial hemorrhage (ICH) were calculated for older (≥80 years) and younger (<80 years) cohorts. RESULTS: We included 32 078 rivaroxaban and 83 971 warfarin users (6606 rivaroxaban and 25,335 warfarin patients were aged ≥80 years). No significant interaction for rivaroxaban versus warfarin by age was observed for any outcome, including SSE (HR = 1.05 vs 0.95), hospitalization for major or CRNMB (HR = 1.06 vs 0.90), vascular death (HR = 0.92 vs 0.90), MALE (HR = 0.80 vs 0.76), major bleeding or ICH. CONCLUSIONS: The effectiveness and safety of rivaroxaban versus warfarin remained consistent across patient age subgroups.

Worsening of kidney function in patients with atrial fibrillation and chronic kidney disease: evidence from the real-world CALLIPER study.

OBJECTIVE: Evidence is needed on the impact of anticoagulation therapy on kidney function in patients with atrial fibrillation (AF). The objective of this analysis, which is part of the CALLIPER study, was to investigate the risk of worsening kidney function with rivaroxaban 15 mg once daily compared with warfarin in patients with AF and moderate-to-severe chronic kidney disease (CKD) in routine clinical practice in the United States. METHODS: CALLIPER was an observational, retrospective, new-user cohort study. Adult patients with AF in the US IBM Watson MarketScan databases who newly initiated anticoagulation with rivaroxaban 15 mg once daily or warfarin between January 2013 and December 2017 were included. Comparative analysis was performed using Cox proportional hazards regression after adjustment for potential confounding by the stabilized inverse probability of treatment weighting approach and propensity score matching. One of the main study outcomes was worsening kidney function (composite of progression to CKD stage 5, kidney failure, or need for dialysis), besides traditional AF-related outcomes. RESULTS: The cohort included 7368 patients: 5903 (80.1%) initiating warfarin and 1465 (19.9%) initiating rivaroxaban 15 mg once daily. Rivaroxaban 15 mg was associated with a significant 47% reduction in the risk of worsening kidney function versus warfarin (hazard ratio 0.53; 95% confidence interval 0.35-0.78). Similar results were observed in the subgroup of patients with type 2 diabetes. CONCLUSIONS: Rivaroxaban 15 mg may be associated with a lower risk of worsening kidney function as compared with warfarin in the atrial fibrillation population with moderate-to-severe CKD. TRIAL REGISTRATION NUMBER: NCT03359876.

Kidney, limb and ophthalmic complications, and death in patients with nonvalvular atrial fibrillation and type 2 diabetes prescribed rivaroxaban or warfarin: an electronic health record analysis.

BACKGROUND: Patients with nonvalvular atrial fibrillation (NVAF) and type 2 diabetes are at risk of kidney, limb, and ophthalmic complications. We evaluated the rate of these complications and death in patients with NVAF and type 2 diabetes prescribed rivaroxaban or warfarin. METHODS: We analyzed Optum de-Identified electronic health record (EHR) data from 11/2010-12/2019. We included adults with NVAF and T2D newly initiated on rivaroxaban or warfarin with ≥12 months of prior EHR activity. Patients with another indication for anticoagulation, valve disease, history of end-stage renal disease, major adverse limb events (MALE), diabetic retinopathy or pregnancy were excluded. We evaluated the incidence rate of developing a composite outcome of >40% decrease in estimated glomerular filtration incidence rate (eGFR) from baseline, eGFR < 15 mL/minute/1.73 m2, need for dialysis or kidney transplant, MALE, diabetic retinopathy or death. Overlap weighting was used to balance baseline characteristics between cohorts while preserving sample size. Hazard ratios with 95% confidence intervals were calculated using propensity score-overlap weighted Cox regression. RESULTS: We included 24,912 rivaroxaban and 58,270 warfarin users. The mean ± standard deviation (SD) CHA2DS2VASc score was 4.3 ± 1.5 and modified HASBLED score was 1.5 ± 0.8. Thirty percent of rivaroxaban patients were started on 15 mg once daily, with the rest prescribed 20 mg once daily. Warfarin patients had a mean time in therapeutic range of 47 ± 28%. Patients were followed for a mean of 2.89 ± 1.95 years. Rivaroxaban was associated with a reduced hazard of the composite outcome (HR = 0.93, 95%CI = 0.91-0.95; absolute risk reduction = 1.97 events per 1000 patient-years; number needed-to-treat = 51) versus warfarin. Rivaroxaban was also associated with significant reductions in the relative hazard of > 40% decrease in eGFR from baseline (HR = 0.96), need for dialysis or renal transplant (HR = 0.81), and limb revascularization or major amputation (HR = 0.85). Death occurred at a lower incidence rate with rivaroxaban (HR = 0.92, 95%CI = 0.89-0.95). CONCLUSIONS: Rivaroxaban was associated with reduced incidence rates of kidney and limb complications, and death in NVAF patients with type 2 diabetes compared to warfarin. ClinicalTrials.gov Identifier: NCT04509193.

Thromboembolism, bleeding and vascular death in nonvalvular atrial fibrillation patients with type 2 diabetes receiving rivaroxaban or warfarin.

BACKGROUND: Diabetes increases a patient's risk of developing atrial fibrillation by 49%. Patients with nonvalvular atrial fibrillation are at a fivefold increased risk of stroke and die more frequently from vascular causes. We sought to evaluate the effectiveness and safety of rivaroxaban versus warfarin in nonvalvular atrial fibrillation patients with type 2 diabetes. METHODS: This was an analysis of Optum® De-Identified electronic health record data from 11/2010 to 12/2019. We included adults with nonvalvular atrial fibrillation and type 2 diabetes, newly started on rivaroxaban or warfarin and with ≥ 12-months of prior electronic health record activity. Patients who were pregnant, had alternative indications for oral anticoagulation or valvular heart disease were excluded. We evaluated the incidence rate (%/year) of developing the composite outcome of stroke/systemic embolism or vascular death and major or clinically relevant nonmajor bleeding as well as each endpoint individually. Hazard ratios with 95% confidence intervals were calculated using propensity score-overlap weighted proportional hazards regression. RESULTS: We included 32,078 rivaroxaban (31% initiated on 15 mg dose) and 83,971warfarin users (time-in-therapeutic range = 47 ± 28%). Rivaroxaban was associated with a reduced risk of stroke/systemic embolism or vascular death (3.79 vs. 4.19; hazard ratio = 0.91, 95% confdience interval = 0.88-0.95), driven mostly by reductions in vascular death (2.81 vs 3.18, hazard ratio = 0.90, 95% confidence interval = 0.86-0.95) and systemic embolism (0.13 vs. 0.16; hazard ratio = 0.82, 95% confidence interval = 0.66-1.02). Major/clinically relevant nonmajor bleeding was less frequent with rivaroxaban versus warfarin (2.17 vs. 2.31; hazard ratio = 0.94, 95% confidence interval = 0.89-0.99) due to decreased critical organ bleeding (including intracranial hemorrhage) (0.35 vs. 0.54; hazard ratio = 0.63, 95% confidence interval = 0.55-0.72). CONCLUSIONS: In nonvalvular atrial fibrillation patients with type 2 diabetes, rivaroxaban was associated with an ~ 10% relative reduction in vascular mortality and fewer bleeding-related hospitalizations versus warfarin.

Dynamic risk assessment to improve quality of care in patients with atrial fibrillation: the 7th AFNET/EHRA Consensus Conference.

AIMS: The risk of developing atrial fibrillation (AF) and its complications continues to increase, despite good progress in preventing AF-related strokes. METHODS AND RESULTS: This article summarizes the outcomes of the 7th Consensus Conference of the Atrial Fibrillation NETwork (AFNET) and the European Heart Rhythm Association (EHRA) held in Lisbon in March 2019. Sixty-five international AF specialists met to present new data and find consensus on pressing issues in AF prevention, management and future research to improve care for patients with AF and prevent AF-related complications. This article is the main outcome of an interactive, iterative discussion between breakout specialist groups and the meeting plenary. AF patients have dynamic risk profiles requiring repeated assessment and risk-based therapy stratification to optimize quality of care. Interrogation of deeply phenotyped datasets with outcomes will lead to a better understanding of the cardiac and systemic effects of AF, interacting with comorbidities and predisposing factors, enabling stratified therapy. New proposals include an algorithm for the acute management of patients with AF and heart failure, a call for a refined, data-driven assessment of stroke risk, suggestions for anticoagulation use in special populations, and a call for rhythm control therapy selection based on risk of AF recurrence. CONCLUSION: The remaining morbidity and mortality in patients with AF needs better characterization. Likely drivers of the remaining AF-related problems are AF burden, potentially treatable by rhythm control therapy, and concomitant conditions, potentially treatable by treating these conditions. Identifying the drivers of AF-related complications holds promise for stratified therapy.

Electrocoagulation of simulated reactive dyebath effluent with aluminum and stainless steel electrodes.

Reactive dyebath effluents are ideal candidates for electrocoagulation due to their intensive color, medium strength, recalcitrant COD and high electrolyte (NaCl) content. The present study focused on the treatability of simulated reactive dyebath effluent (COD(o)=300 mg/L; color in terms of absorbance values A(o,436)=0.532 cm(-1), A(o,525)=0.693 cm(-1) and A(o,620)=0.808 cm(-1)) employing electrocoagulation with aluminum and stainless steel electrodes. Optimization of critical operating parameters such as initial pH (pH(o) 3-11), applied current density (J(c)=22-87 mA/cm(2)) and electrolyte type (NaCl or Na(2)SO(4)) improved the overall treatment efficiencies resulting in effective decolorization (99% using stainless steel electrodes after 60 min, 95% using aluminum electrodes after 90 min electrocoagulation) and COD abatement (93% with stainless steel electrodes after 60 min, 86% with aluminum electrodes after 90 min of reaction time). Optimum electrocoagulation conditions were established as pH(o) 5 and J(c)=22 mA/cm(2) for both electrode materials. The COD and color removal efficiencies also depended on the electrolyte type. No in situ, surplus adsorbable organically bound halogens (AOX) formation associated with the use of NaCl as the electrolyte during electrocoagulation was detected. An economical evaluation was also carried out within the frame of the study. It was demonstrated that electrocoagulation of reactive dyebath effluent with aluminum and stainless steel electrodes was a considerably less electrical energy-intensive, alternative treatment method as compared with advanced chemical oxidation techniques.